Breast cancer is the most common form of cancer in women in the U.S., occurring in 12% of the female population, and is the leading cause of cancer deaths in women under age 55. Current breast cancer therapy typically involves surgical removal of the tumor, followed by radiation or chemotherapy in an attempt to eliminate any tumor cells remaining after surgery. Approximately 50-70% of breast cancers are classified as estrogen receptor alpha (ER) positive, and these patients are treated with tamoxifen, or the related drug raloxifene. Tamoxifen is a selective estrogen receptor modulator (SERM) that inhibits the growth of estrogen receptor-positive, estradiol-dependent breast cancer cells and has been clearly demonstrated to be an effective post-surgery adjuvant to prevent or delay cancer remission. Because of the effectiveness and low toxicity of tamoxifen, essentially all breast cancers are currently tested for ER status. The current standard diagnostic tests are immunohistochemical (IHC) assays, and approximately 200,000 IHC tests are performed annually in the US on breast tumor biopsies. There is considerable variability of assay conditions and reagents between testing labs, as well as different staining cutoffs used in reporting ER positive status. More importantly, these assays merely measure the presence of the protein. A large number of mutations and splice variants of the ER have been observed in breast tumors, and many of these alterations affect protein function. Loss of function, constitutively active (estradiol independent), increased hormone responsiveness and altered cofactor affinity has all been observed. During Phase I research, functional genetic tests of ER status will be developed that are more quantitative and informative than current IHC assays. With these tests, the responsiveness of the tumor specific ER to estradiol, or other hormones, can be measured and, furthermore, the response of individual ER variants to cofactors can be determined. The increased information generated with these new tests will facilitate prescribing the most appropriate (hormonal) therapy for the particular breast cancer. These improved diagnostics should increase the effectiveness of both currently available therapeutics and those developed in the future by matching ER functional status of the breast cancer to available therapeutic compounds.